This invention relates to novel oxathiepino[6,5-b]dihydropyridines useful as calcium channel blockers. These compounds, and related pharmaceutical compositions, are useful for treating and preventing a number of disorders such as hypersensitivity, allergy, asthma, bronchospasm, dysmenorrhea, esophageal spasm, glaucoma, premature labor, urinary tract disorders, gastrointestinal motility disorders and cardiovascular disorders.
Thiacycloalkeno[3,2-b]pyridines are inhibitors of calcium ion uptake into smooth muscle tissue. They act to relax or prevent contraction of the tissue mediated by calcium mechanisms (Dodd et al., Drug Des. Discov. 1997 15:135-48). These compounds are active antihypertensives and bronchodilators.
Thiacycloalkeno[3,2-b]pyridines are also useful for the treatment of cardiovascular disorders, including hypertension, ischemia, angina, congestive heart failure, migraine, myocardial infarction and stroke. Such compounds are also useful for the treatment of other disorders such as hypersensitivity, allergy, asthma, dysmenorrhea, esophageal spasm, gastrointestinal motility disorders, glaucoma, premature labor and urinary tract disorders.
Dodd et al. evaluated a series of thiacycloalkeno[3,2-b]pyridines ranging in sulfone ring size from five to nine membered for calcium antagonist activity. It was found that increasing the sulfone ring size from 5 to 8 members results in an in vitro potency increase of two orders of magnitude. Aromatic substitution patterns which favor tracheal effects over aortic effects were found to be 2-NO2 and 2-Cl, 6-F. The ester side chain which was found to maximize in vivo activity was the N-benzyl-N-methyl aminoethyl moiety (Dodd et al., Drug Des. Discov. 1997, 15:135-48, and Drug Des. Discov. 1993, 10:65-75).
Numerous compounds related to thiacycloalkenopyridines are known, as exemplified by the following publications. U.S. Pat. No. 5,708,177 to Straub discloses a process for the preparation of optically active ortho-substituted 4-aryl-or heteroaryl-1,4-dihydropyridines by oxidation and subsequent reduction from their opposite enantiomers. U.S. Pat. No. 5,075,440 to Wustrow et al. discloses pyrido[2,3-f][1,4]thiazepines and pyrido[3,2-b][1,5]benzothiazepines which are useful as calcium channel antagonists with cardiovascular, antiasthmatic and antibronchoconstriction activity. U.S. Pat. Nos. 4,879,384 and 4,845,225, both to Schwender and Dodd, disclose substituted thiacycloalkeno [3,2-b]pyridines which are also useful as calcium channel antagonists with cardiovascular, antiasthmatic and antibronchoconstrictor activity. U.S. Pat. Nos. 4,285,955 and 4,483,985 disclose acyclic sulfone substitution on simple dihydropyridines which possess calcium channel antagonist activity. U.S. Pat. No. 4,532,248 discloses a broad genus of dihydropyridines, including cyclic sulfones fused to a dihydropyridine nucleus. Cardiotonic activity is disclosed for the entire genus. Finally, 10-Phenyl-2H-thiopyranol[3,2-b]quinolines are disclosed in Pagani, G. P. A., J. Chem. Soc. Perkin Trans. 2, 1392 (1974). However, none of these compounds is a calcium channel antagonist.
xe2x80x9cSoft drugsxe2x80x9d (also known as xe2x80x9cantedrugsxe2x80x9d) are biologically active drugs which are metabolically inactivated after they achieve their therapeutic role at their designed site of action. The use of soft drugs, instead of their non-inactivatable analogs, avoids unwanted side effects. Soft drugs are known generally (see, for example, Biggadike et al., 2000, J. Med. Chem. 43:19-21; Lee et al., 1998, Curr. Opin. Drug Disc. Dev. 1: 235-44). However, no dihydropyridine soft drugs are known.
This invention provides novel compounds classified by Formula I as defined hereinbelow, as well as methods for making same. This invention also provides a pharmaceutical composition comprising the instant compound and a pharmaceutically acceptable carrier.
This invention further provides a method of treating a subject suffering from a disorder whose alleviation is mediated by the reduction of calcium ion influx into cells whose actions contribute to the disorder, which method comprises administering to the subject a therapeutically effective dose of the instant pharmaceutical composition.
This invention still further provides a method of inhibiting in a subject the onset of a disorder whose alleviation is mediated by the reduction of calcium ion influx into cells whose actions contribute to the disorder, which method comprises administering to the subject a prophylactically effective dose of the instant pharmaceutical composition.
Finally, this invention provides an apparatus for administering to a subject the instant pharmaceutical composition, comprising a container and the pharmaceutical composition therein, whereby the container has a means for delivering to the subject a therapeutic and/or prophylactic dose of the pharmaceutical composition.
This invention provides a compound of Formula I, 
or a pharmaceutically acceptable salt thereof, wherein
(a) R1, R2, R3, R4 and R5 are independently selected from the group consisting of H, OH, halogen, cyano, NO2, alkyl, C1-8 alkoxy, C1-8 alkylsulfonyl, C1-4 carboalkoxy, C1-8 alkylthio, difluoromethoxy, difluoromethylthio, trifluoromethyl and oxadiazole (formed by R1 and R2);
(b) R6 is selected from the group consisting of H, C1-5 straight or branched alkyl, aryl, 3-piperidyl, N-substituted 3-piperidyl, N-substituted 2-pyrrolidinyl methylene and substituted alkyl, wherein
said N-substituted 3-piperidyl and said N-substituted 2-pyrrolidinyl methylene may be substituted with C1-8 straight or branched chain alkyl or benzyl, and said substituted alkyl may be substituted with C1-8 alkoxy, C2-8 alkanoyloxy, phenylacetyloxy, benzoyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, carboalkoxy or NRxe2x80x2Rxe2x80x3, wherein
(i) Rxe2x80x2 and Rxe2x80x3 are independently selected from the group consisting of H, C1-8 straight or branched alkyl, C3-7 cycloalkyl, phenyl, benzyl and phenethyl, or
(ii) Rxe2x80x2 and Rxe2x80x3 together form a heterocyclic ring selected from the group consisting of piperidino, pyrrolidino, morpholino, thiomorpholino, piperazino, 2-thieno, 3-thieno and an N-substituted derivative of said heterocyclic rings, said N-substituted derivative being substituted with H, C1-8 straight or branched alkyl, benzyl, benzhydryl, phenyl and/or substituted phenyl (substituted with NO2, halogen, C1-8 straight or branched chain alkyl, C1-8 alkoxy and/or trifluoromethyl);
(c) R7 is selected from the group consisting of H, amino, alkyl, aryl, trifluoromethyl, alkoxymethyl, 2-thieno and 3-thieno;
(d) R9 is oxygen or sulfur; and
(e) n is an integer from 1 to 4.
In one embodiment of the instant compound R6 is xe2x80x94(CH2)2N(CH3)CH2Ph or methyl. In a further embodiment, R1, R2, R3, R4 and R5 are independently selected from the group consisting of H, halogen and NO2. In the preferred embodiment, R9 is oxygen.
The following compounds are exemplary of the present invention.
Compound 1: 5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 2,3,6,9-tetrahydro-7-methyl-9-(3-nitrophenyl), 2-[methyl(phenylmethyl)amino]ethyl ester, 1,1-dioxide. 
Compound 2: 5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chlorophenyl)-2,3,6,9-tetrahydro-7-methyl, methyl ester, 1,1-dioxide. 
Compound 3: 5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chlorophenyl)-2,3,6,9-tetrahydro-7-methyl, 2-[methyl(phenylmethyl)amino]ethyl ester, 1,1-dioxide. 
Compound 4: 5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 2,3,6,9-tetrahydro-7-methyl-9-(3-nitrophenyl), methyl ester, 1,1-dioxide. 
Compound 5: 5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 2,3,6,9-tetrahydro-7-methyl-9-(2-nitrophenyl), methyl ester, 1,1-dioxide. 
Compound 6: 5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(3-chlorophenyl)-2,3,6,9-tetrahydro-7-methyl, methyl ester, 1,1-dioxide. 
Compound 7: 5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(3-chlorophenyl)-2,3,6,9-tetrahydro-7-methyl, 2-[methyl(phenylmethyl)amino]ethyl ester, 1,1-dioxide. 
Compound 8: 5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 2,3,6,9-tetrahydro-7-methyl-9-(2-nitrophenyl), 2-[methyl(phenylmethyl)amino]ethyl ester, 1,1-dioxide. 
Compound 9: 5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl, 2-[methyl(phenylmethyl)amino]ethyl ester, 1,1-dioxide. 
This invention also provides soft drug analogs of the compounds of Formula I. These soft drugs are characterized by a chemically labile moiety bound to the ester group in turn bound to the dihydropyridine ring structure. The soft drugs permit the instant drugs to exert their effect locally, and to subsequently be metabolized in the blood stream, thereby reducing unwanted systemic effects (e.g. low blood pressure). Use of such soft drug analogs permits the administration of greater doses of the claimed dihydropyridine compounds without subjecting the subject to intolerable levels of unwanted systemic effects.
Specifically, this invention provides a compound of Formula II, 
or a pharmaceutically acceptable salt thereof, wherein
(a) R1, R2, R3, R4, and R5 are independently selected from the group consisting of hydrogen, OH, halogen, cyano, NO2, alkyl, C1-8 alkoxy, C1-8 alkylsulfonyl, C1-4 carboalkoxy, C1-8 alkylthio, difluoromethoxy, difluoromethylthio, trifluoromethyl and oxadiazole (formed by R1 and R2);
(b) R7 is selected from the group consisting of hydrogen, amino, alkyl, aryl, trifluoromethyl, alkoxymethyl, 2-thieno and 3-thieno;
(c) R8 is selected from the group consisting of -alkyl-OH, alkylamine, lactone, cyclic carbonate, alkyl-substituted cyclic carbonate, aryl-substituted cyclic carbonate, -aryl-C(O)ORxe2x80x2, -alkyl-aryl-C(O)ORxe2x80x2, -alkyl-OC(O)Rxe2x80x2, -alkyl-C(O)Rxe2x80x2, -alkyl-C(O)ORxe2x80x2, -alkyl-N(Rxe2x80x2)C(O)Rxe2x80x2, and -alkyl-N(Rxe2x80x2)C(O)ORxe2x80x2, wherein
Rxe2x80x2 and Rxe2x80x3 are independently selected from the group consisting of hydrogen, amino, alkyl, aryl, aryl-fused cycloalkyl and heterocyclyl, the amino, alkyl, aryl, aryl-fused cycloalkyl and heterocyclyl being optionally substituted with halogen, cyano, NO2, lactone, amino, alkylamino, aryl-substituted alkylamino, amide, carbamate, carbamoyl, cyclic carbonate, alkyl, halogen-substituted alkyl, arylalkyl, alkoxy, heterocyclyl and/or aryl (the aryl being optionally substituted with OH, halogen, cyano, NO2, alkyl, amino, dimethylamino, alkoxy, alkylsulfonyl, C1-4 carboalkoxy, alkylthio and/or trifluoromethyl); and
(d) R9 is oxygen or sulfur.
Each of the preferred embodiments of the compounds of Formula I set forth above is also contemplated as an embodiment of the compounds of Formula II. In addition, in a preferred embodiment of the compound of Formula II, R8 is selected from -alkyl-OH, lactone, cyclic carbonate, alkyl-substituted cyclic carbonate, aryl-substituted cyclic carbonate, and -alkyl-OC(O)Rxe2x80x2 wherein Rxe2x80x2 is as described above.
The following compounds (referred to herein as compound nos. 10-19) are also preferred embodiments of the present invention:
5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2,3-dichlorophenyl)-2,3,6,9-tetrahydro-7-methyl-, (5-methyl-2-oxo-1,3-dioxol4-yl)methyl ester, 1,1-dioxide;
5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2,3-dichlorophenyl)-2,3,6,9-tetrahydro-7-methyl-, (2-oxo-5-phenyl-1,3-dioxol-4-yl)methyl ester, 1,1-dioxide;
5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chlorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-hydroxyethyl ester, 1,1-dioxide;
5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chlorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-(2-methyl-1-oxopropoxy)ethyl ester, 1,1-dioxide;
5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-(2-methyl-1-oxopropoxy)ethyl ester, 1,1-dioxide;
5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-[(cyclopropylcarbonyl)oxy]ethyl ester, 1,1-dioxide;
5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-(acetyloxy)ethyl ester, 1,1-dioxide;
5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-[(cyclohexylcarbonyl)oxy]ethyl ester, 1,1-dioxide;
5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-(benzoyloxy)ethyl ester, 1,1-dioxide; and
5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chlorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 3-(benzoyloxy)propyl ester, 1,1-dioxide.
Unless specified otherwise, the term xe2x80x9calkylxe2x80x9d refers to a straight, branched or cyclic substituent consisting solely of carbon and H with no unsaturation. The term xe2x80x9calkoxyxe2x80x9d refers to O-alkyl where alkyl is as defined supra. Illustrative aryl substituents include, for example, phenyl, naphthyl, diphenyl, fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl, carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl,,methoxyethylphenyl, acetamidophenyl, tolyl, xylyl, dimethylcarbamylphenyl, xe2x80x94(CH2)2N(CH3)CH2Ph, xe2x80x94CH2CH2xe2x80x94N(Me)xe2x80x94CH2-heteroaryl and the like. The term xe2x80x9chaloxe2x80x9d means fluoro, chloro, bromo and iodo. The symbol xe2x80x9cPhxe2x80x9d refers to phenyl. xe2x80x9cIndependentlyxe2x80x9d means that when there are more than one substituent, the substitutents may be different.
The compounds of the instant invention are asymmetric in the dihydropyridine ring at the 4-position and thus exist as optical antipodes. As such, all possible optical isomers, antipodes, enantiomers or diastereomers resulting from additional asymmetric centers that may exist in optical antipodes, racemates and racemic mixtures thereof are also part of this invention. The antipodes can be separated by methods known to those skilled in the art such as, for example, fractional recrystallization of diastereomeric salts of enantiomerically pure acids. Alternatively, the antipodes can be separated by chromatography in a Pirkle type column.
As used herein, the phrase xe2x80x9cpharmaceutically acceptable saltxe2x80x9d means a salt of the free base which possesses the desired pharmacological activity of the free base and which is neither biologically nor otherwise undesirable. These salts may be derived from inorganic or organic acids. Examples of inorganic acids are hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid, and phosphoric acid. Examples of organic acids are acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, methyl sulfonic acid, salicyclic acid and the like.
The instant compounds can be prepared using readily available starting materials. The first step of the synthesis as shown hereinafter in Scheme I is well known in the art (Shibata et al., Fuji Photo Film Co., Ltd., Jpn. Kokai Tokkyo Koho, p. 47; JP Patent 62253161, 1987; JP Patent Application 86-39760 (860224); Canadian Patent Application No. 429975, 1988).
This invention also provides a pharmaceutical composition comprising the instant compound and a pharmaceutically acceptable carrier.
Pharmaceutical compositions containing a compound of the present invention as the active ingredient in intimate admixture with a pharmaceutical carrier can be prepared according to conventional pharmaceutical techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, such as systemic administration, including but not limited to intravenous, oral, nasal or parenteral. In preparing the compositions in oral dosage form, any of the usual pharmaceutical carriers may be employed, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, syrup and the like in the case of oral liquid preparations (for example, suspensions, elixirs and solutions), or carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations (for example, powders, capsules and tablets).
In a particular embodiment, the compounds of the instant invention are administered by inhalation. For inhalation therapy, the compound may be in a solution useful for administration by metered dose inhalers, or in a form suitable for a dry powder inhaler or insufflator. More particularly, the compounds for use in accordance with the present invention are conveniently delivered in the form of an aerosol spray presentation from a pressurized container, a pack or a nebuliser, for instance, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas inside such container. The dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges made of a pharmaceutically acceptable material such as gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
Because of their ease of administration, tablets and capsules represent an advantageous oral dosage unit form, wherein solid pharmaceutical carriers are employed. If desired, tablets may be sugar-coated or enteric-coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, though other ingredients for solubility or preservative purposes may also be included. Injectable suspensions may also be prepared, wherein appropriate liquid carriers, suspending agents and the like may be employed. The compounds may also be administered in the form of an aerosol.
The instant pharmaceutical compositions will generally contain a per dosage unit (e.g., tablet, capsule, powder, injection, teaspoonful and the like) from about 0.001 to about 100 mg/kg, and preferably from about 0.01 to about 20 mg/kg of the instant compound. Methods are known in the art for determining therapeutically and prophylactically effective doses for the instant pharmaceutical composition. The effective dose for administering the pharmaceutical composition to a human, for example, can be determined mathematically from the results of animal studies.
The compounds of the present invention inhibit the uptake of calcium ions into smooth muscle, and therefore act to relax or prevent calcium ion-mediated contraction of smooth muscle tissue.
Thus, this invention further provides a method of treating a subject suffering from a disorder whose alleviation is mediated by the reduction of calcium ion influx into cells whose actions contribute to the disorder, which method comprises administering to the subject a therapeutically effective dose of the instant pharmaceutical composition. By way of example, in a subject suffering from asthma, the subject""s airways are constricted due to contraction of airway smooth muscle cells (xe2x80x9cSMC""sxe2x80x9d). Reducing the calcium influx into the SMC""s, whose action contributes to the disorder, would be expected to alleviate the disorder.
This invention still further provides a method of inhibiting in a subject the onset of a disorder whose alleviation is mediated by the reduction of calcium ion influx into cells whose actions contribute to the disorder, which method comprises administering to the subject a prophylactically effective dose of the instant pharmaceutical composition.
In one embodiment, the disorder is selected from the group consisting of hypersensitivity, allergy, asthma, bronchospasm, dysmenorrhea, esophageal spasm, glaucoma, premature labor, a urinary tract disorder, a gastrointestinal motility disorder and a cardiovascular disorder. In the preferred embodiment, the disorder is asthma. The cardiovascular disorder can be, for example, hypertension, ischemia, angina, congestive heart failure, myocardial infarction or stroke.
As used herein, xe2x80x9ctreatingxe2x80x9d a disorder means eliminating or otherwise ameliorating the cause and/or effects thereof. xe2x80x9cInhibitingxe2x80x9d the onset of a disorder means preventing, delaying or reducing the likelihood of such onset.
The term xe2x80x9csubjectxe2x80x9d includes, without limitation, any animal or artificially modified animal. In the preferred embodiment, the subject is a human.
This invention further provides an apparatus for administering to a subject the instant pharmaceutical composition, comprising a container and the pharmaceutical composition therein, whereby the container has a means for delivering to the subject a therapeutic and/or prophylactic dose of the pharmaceutical composition. In the preferred embodiment, the apparatus is an aerosol spray device for treating and/or preventing asthma via topical respiratory administration.
Finally, as set forth in more detail below, this invention provides a process for preparing the compound of Formula I: 
This invention will be better understood by reference to the Experimental Details that follow, but those skilled in the art will readily appreciate that these are only illustrative of the invention as described more fully in the claims which follow thereafter. Additionally, throughout this application, various publications are cited. The disclosure of these publications is hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains.
A. Schemes and Syntheses
Procedures for making dihydropyridines are well documented in the art as shown in Eistert et al. (Chem. Ber. 110, 1069-1085,1977), G. A. Pagani (J. Chem. Soc., Perkin Trans. 2, 1392-7, 1974), Mason et al. (J. Chem. Soc. (C) 2171-76, 1967), E. A. Fehnel (J. Amer. Chem. Soc. 74, 1569-74, 1952), and M. Seiyaku (Japan Patent Application No. 58201764, 1984).
Scheme I shows the preparation of the compounds of Formula I: 
The compounds of Formula II can be made in accordance with Scheme II (wherein compound 2a may be made in steps analogous to those in Scheme I and R1-9 are as described above), preferably in the presence of K2CO3or CsCO3 in an organic solvent such as dimethylformamide (DMF). 
The compounds of Formula 11 may also be made in accordance with Scheme III (wherein compound 3a may be made in steps analogous to those in Scheme 1, and R1-9 are as described above), preferably in the presence of formic acid or NaOH (aq), respectively. 
The following examples describe in greater particularity the chemical synthesis of representative compounds of the present invention. The remaining compounds disclosed herein can be prepared similarly in accordance with one or more of these methods. No attempt has been made to optimize the yields obtained in these reactions, and it would be clear to one skilled in the art that variations in reaction times, temperatures, solvents and/or reagents could increase the yields.